Head and neck cancer presents primarily as head and neck squamous cell carcinoma (HNSCC), a debilitating malignancy fraught with high morbidity, poor survival rates, and limited treatment options. Mounting evidence indicates that the Wnt/Î²-catenin signaling pathway plays important roles in the pathobiology of HNSCC. Wnt/Î²-catenin signaling affects multiple cellular processes that endow cancer cells with the ability to maintain and expand immature stem-like phenotypes, proliferate, extend survival, and acquire aggressive characteristics by adopting mesenchymal traits. A central component of canonical Wnt signaling is Î²-catenin, which balances its role as a structural component of E-cadherin junctions with its function as a transcriptional coactivator of numerous target genes. Recent genomic characterization of head and neck cancer revealed that while Î²-catenin is not frequently mutated in HNSCC, its activity is unchecked by more common mutations in genes encoding upstream regulators of Î²-catenin, NOTCH1, FAT1, and AJUBA. Wnt/Î²-catenin signaling affects a wide range epigenetic and transcriptional activities, mediated by the interaction of Î²-catenin with different transcription factors and transcriptional coactivators and corepressors. Furthermore, Wnt/Î²-catenin functions in a network with many signaling and metabolic pathways that modulate its activity. In addition to its effects on tumor epithelia, Î²-catenin activity regulates the tumor microenvironment by regulating extracellular matrix remodeling, fibrotic processes, and immune response. These multifunctional oncogenic effects of Î²-catenin make it an attractive bona fide target for HNSCC therapy.]]>Wed, 31 Dec 1969 19:00:00 ESTThe effects of DNA methylation on human psychology.Kader F, Ghai M, Maharaj LBehav Brain Res (07 2018)

DNA methylation is a fundamental epigenetic modification in the human genome; pivotal in development, genomic imprinting, X inactivation, chromosome stability, gene expression and methylation aberrations are involved in an array of human diseases. Methylation at promoters is associated with transcriptional repression, whereas gene body methylation is generally associated with gene expression. Extrinsic factors such as age, diets and lifestyle affect DNA methylation which consequently alters gene expression. Stress, anxiety, depression, life satisfaction, emotion among numerous other psychological factors also modify DNA methylation patterns. This correlation is frequently investigated in four candidate genes; NR3C1, SLC6A4, BDNF and OXTR, since regulation of these genes directly impact responses to social situations, stress, threats, behaviour and neural functions. Such studies underpin the hypothesis that DNA methylation is involved in deviant human behaviour, psychological and psychiatric conditions. These candidate genes may be targeted in future to assess the correlation between methylation, social experiences and long-term behavioural phenotypes in humans; and may potentially serve as biomarkers for therapeutic intervention.]]>Wed, 31 Dec 1969 19:00:00 ESTEnrichment analysis with EpiAnnotator.Pageaud Y, Plass C, Assenov YBioinformatics (May 2018)

Deciphering relevant biological insights from epigenomic data can be a challenging task. One commonly used approach is to perform enrichment analysis. However, finding, downloading and using the publicly available functional annotations require time, programming skills and IT infrastructure. Here we describe the online tool EpiAnnotator for performing enrichment analyses on epigenomic data in a fast and user-friendly way.]]>Wed, 31 Dec 1969 19:00:00 ESTImpact of dietary gut microbial metabolites on the epigenome.Gerhauser CPhilos Trans R Soc Lond B Biol Sci (Jun 2018)

Within the past decade, epigenetic mechanisms and their modulation by natural products have gained increasing interest. Dietary bioactive compounds from various sources, including green tea, soya, fruit and berries, cruciferous vegetables, whole grain foods, fish and others, have been shown to target enzymes involved in epigenetic gene regulation, including DNA methyltransferases, histone acetyltransferases, deacetylases and demethylases and in cell culture. Also, many dietary agents were shown to alter miRNA expression. studies in animal models and humans are still limited. Recent research has indicated that the gut microbiota and gut microbial metabolites might be important mediators of diet-epigenome interactions. Inter-individual differences in the gut microbiome might affect release, metabolism and bioavailability of dietary agents and explain variability in response to intervention in human studies. Only a few microbial metabolites, including folate, phenolic acids, -(-)equol, urolithins, isothiocyanates, and short- and long-chain fatty acids have been tested with respect to their potential to influence epigenetic mechanisms. Considering that a complex mixture of intermediary and microbial metabolites is present in human circulation, a more systematic interdisciplinary investigation of nutri-epigenetic activities and their impact on human health is called for.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.]]>Wed, 31 Dec 1969 19:00:00 ESTIntegrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes.Wolters JEJ, van Breda SGJ, Grossmann J, Fortes C, Caiment F, Kleinjans JCSToxicol Lett (Jun 2018)

Cancer is an aging-associated disease, but the underlying molecular links between these processes are still largely unknown. Gene promoters that become hypermethylated in aging and cancer share a common chromatin signature in ES cells. In addition, there is also global DNA hypomethylation in both processes. However, the similarity of the regions where this loss of DNA methylation occurs is currently not well characterized, and it is unknown if such regions also share a common chromatin signature in aging and cancer. To address this issue, we analyzed TCGA DNA methylation data from a total of 2,311 samples, including control and cancer cases from patients with breast, kidney, thyroid, skin, brain, and lung tumors and healthy blood, and integrated the results with histone, chromatin state, and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects. We identified 98,857 CpG sites differentially methylated in aging and 286,746 in cancer. Hyper- and hypomethylated changes in both processes each had a similar genomic distribution across tissues and displayed tissue-independent alterations. The identified hypermethylated regions in aging and cancer shared a similar bivalent chromatin signature. In contrast, hypomethylated DNA sequences occurred in very different chromatin contexts. DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging, while in cancer, loss of DNA methylation was primarily associated with the repressive H3K9me3 mark. Our results suggest that the role of DNA methylation as a molecular link between aging and cancer is more complex than previously thought.]]>Wed, 31 Dec 1969 19:00:00 ESTGWAS4D: multidimensional analysis of context-specific regulatory variant for human complex diseases and traits.Huang D, Yi X, Zhang S, Zheng Z, Wang P, Xuan C, Sham PC, Wang J, Li MJNucleic Acids Res (May 2018)

Eusocial insects exhibit the most striking example of phenotypic plasticity. There has been a long controversy over the factors determining caste development of individuals in social insects. Here we demonstrate that parental phenotypes influence the social status of offspring not through genetic inheritance but through genomic imprinting in termites. Our extensive field survey and genetic analysis of the termite Reticulitermes speratus show that its breeding system is inconsistent with a genetic caste determination model. We therefore developed a genomic imprinting model, in which queen- and king-specific epigenetic marks antagonistically influence sexual development of offspring. The model accounts for all known empirical data on caste differentiation of R. speratus and other related species. By conducting colony-founding experiments and additively incorporating relevant socio-environmental factors into our genomic imprinting model, we show the relative importance of genomic imprinting and environmental factors in caste determination. The idea of epigenetic inheritance of sexual phenotypes solves the puzzle of why parthenogenetically produced daughters carrying only maternal chromosomes exclusively develop into queens and why parental phenotypes (nymph- or worker-derived reproductives) strongly influence caste differentiation of offspring. According to our model, the worker caste is seen as a "neuter" caste whose sexual development is suppressed due to counterbalanced maternal and paternal imprinting and opens new avenues for understanding the evolution of caste systems in social insects.]]>Wed, 31 Dec 1969 19:00:00 EST'Omic' technologies as a helpful tool in radioecological research.Volkova PY, Geras'kin SAJ Environ Radioact (Sep 2018)

In the setting of Cushing syndrome, genomic analyses can be performed either in tumors responsible for endogenous Cushing, or in patients exposed to glucocorticoid excess. Genomics of tumors identified several new genes - including ZNRF3 in adrenocortical carcinomas, PRKACA in cortisol-producing adrenal adenomas, ARMC5 in primary macronodular adrenal hyperplasia and USP8 in pituitary corticotroph adenomas. These genes shed new lights on the mechanisms responsible for these tumors. Integrated genomic studies of adrenal carcinomas identified distinct molecular classes, with remarkably different prognostic outcome. Beyond the mechanistic novelties, a new generation of prognostic markers emerges, with potentially important impact on patients care. For the future, genomic efforts should be pursued, focusing on poorly characterized tumors responsible for Cushing syndromeÂ -Â including endocrine tumors secreting ACTH. In addition, epigenomics is emerging as an outstanding set of tools for characterizing tumors, unraveling unprecedented aspects of tumorigenesis. Applying these tools to endocrine tumors responsible for Cushing syndrome may also lead to important discoveries. Genomics of patients exposed to glucocorticoid excess is an emerging research field. Proof of principle studies have been performed, identifying molecular markers of glucocorticoid excess in blood. Research efforts should now concentrate on markers of mild glucocorticoid excessesÂ -Â endogenous or exogenousÂ -, owing to their high prevalence in general population. In addition, markers of individual susceptibility to each type of glucocorticoid complication are needed. It remains to be determined whether genomics can identify such markers.]]>Wed, 31 Dec 1969 19:00:00 ESTFunctional analyses of PtRDM1 gene overexpression in poplars and evaluation of its effect on DNA methylation and response to salt stress.Movahedi A, Zhang J, Sun W, Mohammadi K, Almasi Zadeh Yaghuti A, Wei H, Wu X, Yin T, Zhuge QPlant Physiol Biochem (Jun 2018)

Temple syndrome (TS14, #616222) is a rare imprinting disorder characterised by phenotypic features including pre- and postnatal growth retardation, muscular hypotonia and feeding difficulties in infancy, early puberty and short stature with small hands and feet and often truncal obesity. It is caused by maternal uniparental disomies, paternal deletions and primary imprinting defects that affect the chromosomal region 14q32 and lead to a disturbed expression of imprinted genes in this region. Here, we present detailed clinical data of 8 patients with Temple syndrome, 4 with an imprinting defect, 2 with an imprinting defect in a mosaic state as well as 1 complete and 1 segmental maternal uniparental disomy of chromosome 14.]]>Wed, 31 Dec 1969 19:00:00 ESTPolymorphic Imprinting of SLC38A4 Gene in Bovine Placenta.Xu D, Zhang C, Li J, Wang G, Chen W, Li D, Li SBiochem Genet (May 2018)

Imprinted genes are characterized by monoallelic expression that is dependent on parental origin. Comparative analysis of imprinted genes between species is a powerful tool for understanding the biological significance of genomic imprinting. The slc38a4 gene encodes a neutral amino acid transporter and is identified as imprinted in mice. In this study, the imprinting status of SLC38A4 was assessed in bovine adult tissues and placenta using a polymorphism-based approach. Results indicate that SLC38A4 is not imprinted in eight adult bovine tissues including heart, liver, spleen, lung, kidney, muscle, fat, and brain. It was interesting to note that SLC38A4 showed polymorphic status in five heterogeneous placentas, with three exhibiting paternal monoallelic expression and two exhibiting biallelic expression. Monoallelic expression of imprinted genes is generally associated with allele-specific differentially methylation regions (DMRs) of CpG islands (CGIs)-encompassed promoter; therefore, the DNA methylation statuses of three CGIs in the SLC38A4 promoter and exon 1 region were tested in three placentas (two exhibiting paternal monoallelic and one showing biallelic expression of SLC38A4) and their corresponding paternal sperms. Unexpectedly, extreme hypomethylation (Wed, 31 Dec 1969 19:00:00 ESTOxygen-induced alterations in the expression of chromatin modifying enzymes and the transcriptional regulation of imprinted genes.Skiles WM, Kester A, Pryor JH, Westhusin ME, Golding MC, Long CRGene Expr Patterns (Jun 2018)

Embryo culture and assisted reproductive technologies have been associated with a disproportionately high number of epigenetic abnormalities in the resulting offspring. However, the mechanisms by which these techniques influence the epigenome remain poorly defined. In this study, we evaluated the capacity of oxygen concentration to influence the transcriptional control of a selection of key enzymes regulating chromatin structure. In mouse embryonic stem cells, oxygen concentrations modulated the transcriptional regulation of the TET family of enzymes, as well as the de novo methyltransferase Dnmt3a. These transcriptional changes were associated with alterations in the control of multiple imprinted genes, including H19, Igf2, Igf2r, and Peg3. Similarly, exposure of in vitro produced bovine embryos to atmospheric oxygen concentrations was associated with disruptions in the transcriptional regulation of TET1, TET3, and DNMT3a, along with the DNA methyltransferase co-factor HELLS. In addition, exposure to high oxygen was associated with alterations in the abundance of transcripts encoding members of the Polycomb repressor complex (EED and EZH2), the histone methyltransferase SETDB1 and multiple histone demethylases (KDM1A, KDM4B, and KDM4C). These disruptions were accompanied by a reduction in embryo viability and suppression of the pluripotency genes NANOG and SOX2. These experiments demonstrate that oxygen has the capacity to modulate the transcriptional control of chromatin modifying genes involved in the establishment and maintenance of both pluripotency and genomic imprinting.]]>Wed, 31 Dec 1969 19:00:00 ESTDistinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes.Lomberk G, Blum Y, Nicolle R, Nair A, Gaonkar KS, Marisa L, Mathison A, Sun Z, Yan H, Elarouci N, Armenoult L, Ayadi M, Ordog T, Lee JH, Oliver G, Klee E, Moutardier V, Gayet O, Bian B, Duconseil P, Gilabert M, Bigonnet M, Garcia S, Turrini O, Delpero JR, Giovannini M, Grandval P, Gasmi M, Secq V, De ReyniÃ¨s A, Dusetti N, Iovanna J, Urrutia RNat Commun (May 2018)

Immunotherapy strategies targeting immune checkpoints such as the and (programmed cell death 1 ligand 1, PD-L1)/ (programmed cell death 1, PD-1) T-cell coreceptor pathways are revolutionising oncology. The approval of pembrolizumab use for solid tumours with high-level microsatellite instability or mismatch repair deficiency by the US Food and Drug Administration highlights promise of precision immuno-oncology. However, despite evidence indicating influences of exogenous and endogenous factors such as diet, nutrients, alcohol, smoking, obesity, lifestyle, environmental exposures and microbiome on tumour-immune interactions, integrative analyses of those factors and immunity lag behind. Immune cell analyses in the tumour microenvironment have not adequately been integrated into large-scale studies. Addressing this gap, the transdisciplinary field of molecular pathological epidemiology (MPE) offers research frameworks to integrate tumour immunology into population health sciences, and link the exposures and germline genetics (eg, genotypes) to tumour and immune characteristics. Multilevel research using bioinformatics, in vivo pathology and omics (genomics, epigenomics, transcriptomics, proteomics and metabolomics) technologies is possible with use of tissue, peripheral blood circulating cells, cell-free plasma, stool, sputum, urine and other body fluids. This immunology-MPE model can synergise with experimental immunology, microbiology and systems biology. GI neoplasms represent exemplary diseases for the immunology-MPE model, given rich microbiota and immune tissues of intestines, and the well-established carcinogenic role of intestinal inflammation. Proof-of-principle studies on colorectal cancer provided insights into immunomodulating effects of aspirin, vitamin D, inflammatory diets and omega-3 polyunsaturated fatty acids. The integrated immunology-MPE model can contribute to better understanding of environment-tumour-immune interactions, and effective immunoprevention and immunotherapy strategies for precision medicine.]]>Wed, 31 Dec 1969 19:00:00 ESTContemporary trends emerging in epigenomics and metabolism.El-Osta AAntioxid Redox Signal (May 2018)

Diabetes is the disease of our time. It is a complex disorder. It is increasingly appreciated that genetic factors cannot fully explain susceptibility to diabetic complications. For almost a decade, the epigenetics field has grown tremendously becoming an alternative but integral component of how we interpret gene regulation. Some consider the field an epiphenomenon with an evidence base awaiting critical testing. The advent of experimental tools combined with the development of research methods have brought with the field technological advancements that allow scientists to assess ideas that have not yet been tested critically. If there was ever a time not to give up on epigenetics than that time would be now. Under the seeming disorder of more than 3 billion base pairs, the human genome works successfully with order. It is a complex order. Instructed by a chemical code that is largely uncharted in metabolic disease, developmental studies have clearly shown code-exclusivity is key to unlocking the genetic blueprint. Central to this chemical code are specific modifications to DNA and RNA, histones and non-histone proteins; tiny chemical marks that have wide-ranging functions. Robustness is key, and these marks are written to be precisely read and accurately erased.]]>Wed, 31 Dec 1969 19:00:00 ESTCRISPR and personalized Treg therapy: new insights into the treatment of rheumatoid arthritis.Safari F, Farajnia S, Arya M, Zarredar H, Nasrolahi AImmunopharmacol Immunotoxicol (Jun 2018)

Rheumatoid arthritis (RA), as one of the most disabling autoimmune diseases, is a common health problem that progressively reduces the life quality of patients. Although various biologics have been introduced for RA, attempts to establish an efficient long-term therapies failed due to the heterogeneity of this disease.]]>Wed, 31 Dec 1969 19:00:00 ESTFACT complex is required for DNA demethylation at heterochromatin during reproduction in .Frost JM, Kim MY, Park GT, Hsieh PH, Nakamura M, Lin SJH, Yoo H, Choi J, Ikeda Y, Kinoshita T, Choi Y, Zilberman D, Fischer RLProc Natl Acad Sci U S A (May 2018)

The DEMETER (DME) DNA glycosylase catalyzes genome-wide DNA demethylation and is required for endosperm genomic imprinting and embryo viability. Targets of DME-mediated DNA demethylation reside in small, euchromatic, AT-rich transposons and at the boundaries of large transposons, but how DME interacts with these diverse chromatin states is unknown. The STRUCTURE SPECIFIC RECOGNITION PROTEIN 1 (SSRP1) subunit of the chromatin remodeler FACT (facilitates chromatin transactions), was previously shown to be involved in the DME-dependent regulation of genomic imprinting in endosperm. Therefore, to investigate the interaction between DME and chromatin, we focused on the activity of the two FACT subunits, SSRP1 and SUPPRESSOR of TY16 (SPT16), during reproduction in We found that FACT colocalizes with nuclear DME in vivo, and that DME has two classes of target sites, the first being euchromatic and accessible to DME, but the second, representing over half of DME targets, requiring the action of FACT for DME-mediated DNA demethylation genome-wide. Our results show that the FACT-dependent DME targets are GC-rich heterochromatin domains with high nucleosome occupancy enriched with H3K9me2 and H3K27me1. Further, we demonstrate that heterochromatin-associated linker histone H1 specifically mediates the requirement for FACT at a subset of DME-target loci. Overall, our results demonstrate that FACT is required for DME targeting by facilitating its access to heterochromatin.]]>Wed, 31 Dec 1969 19:00:00 EST